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<p dir="ltr">16 Bacterial defense systems against bacteriophage infection build the prokaryotic immune</p><p dir="ltr">17 system and their proper regulation is vital for survival and fitness. While it is important that</p><p dir="ltr">18 they are readily available in case of infection, in the absence of phage they need to be tightly</p><p dir="ltr">19 controlled to prevent activation of an unwanted drastic cellular response. Here we describe</p><p dir="ltr">20 how the bacterial cyclic oligonucleotide-based antiphage signalling system (CBASS) uses its</p><p dir="ltr">21 intrinsic protein modification system to regulate the activity of the CD-NTase (cGAS/DncV-like</p><p dir="ltr">22 nucleotidyl-transferase). By integrating a Type II CBASS system from Bacillus cereus into the</p><p dir="ltr">23 cognate host Bacillus subtilis, we show that the CD-NTase-associated protein 2 (Cap2)</p><p dir="ltr">24 conjugates the CD-NTase exclusively to the conserved phage shock protein A (PspA) in the</p><p dir="ltr">25 absence of phage. We further demonstrate that this CD-NTase-PspA conjugation is reversed</p><p dir="ltr">26 after infection by the endopeptidase Cap3 (CD-NTase-associated protein 3). Finally, we</p><p dir="ltr">27 propose a model in which the cyclase is inhibited by conjugation to PspA in the absence of</p><p dir="ltr">28 phage and that this conjugation is released upon infection, priming the CD-NTase for</p><p dir="ltr">29 activation.</p>